A large number of diseases, including allergic, infectious and autoimmune, positively correlate with either CD4+ Th1 or Th2 effector T-cells. Th1 cells are characterized by the production of proinflammatory cytokines such as INF-gamma and TNF-alpha while Th2 cells secrete IL-4, IL-5, IL-10 and IL-13. Signaling through the histamine H1 receptor (Hrh1/H1R) has been shown to influence the development and regulation of Th1 cells. Importantly, H1R signaling in CD4+ T-cells directly enhances Th1 responses. Recently, Bphs, an autoimmune disease susceptibility locus in experimental allergic encephalomyelitis (EAE), the principal animal model of multiple sclerosis (MS), and autoimmune orchitis, both of which are primarily Th1 mediated, was shown by a positional candidate gene cloning approach to be H1R. Bphs/Hrh1-susceptible and -resistant alleles differ by three amino acids within the third intracytoplasmic domain associated with receptor coupling to the Gq/11-family of G-alpha proteins. The resistant allele possesses a L263, M313 and S331 whereas the susceptible allele is characterized by P263, V313 and P331. This suggests that at least one of these amino acids is critical in coupling H1R to Gq/11-second messenger signaling pathways. Mice possessing either a resistant Bphs/Hrh1 allele or a disrupted gene (HIRKO) exhibit less intense delayed type hypersensitivity responses and are less susceptible to acute EAE. The delay in EAE onset and reduction in severity are associated with immune deviation towards a strongly biased Th2 response. These results indicate that H1R signaling in CD4+ T-cells plays an important role in eliciting Th1 effector cells. To test this hypothesis we will: (1) assess the roles of residues 263, 313, and 331 in coupling H1R to Gq/11; (2) we will transduce Bphs alleles into CD4+ T-cells from H1RKO mice using a retroviral system and assess their roles in immune deviation, and generate transgenic mice expressing the various alleles under the control of the distal Ick promoter which drives expression in mature T-cells; (3) test the hypothesis that H1R signaling augments the activation of NF-kB leading to IFN-gamma production and the generation of Th1 effector cell functions; and (4) examine the role of Shs, an SJL/J specific quantitative trait locus linked to Hrh1 controlling spontaneous sensitivity to histamine elicited by signaling through H1R, in regulating the Th1-biased CD4+ T-cell response to neuroantigens seen in these mice.